AIM: To study the main environmental and lifestyle factors that account for the regional differences in esophageal cancer (EC) risk in low- and high-risk areas of Jiangsu Province, China.METHODS: Since 2003, a population-based casecontrol study has been conducted simultaneously in lowrisk (Ganyu County) and high-risk (Dafeng County) areas of Jiangsu Province, China. Using identical protocols and pre-tested standardized questionnaire, following written informed consent, eligible subjects were inquired about their detail information on potential determinants of EC, including demographic information, socio-economic status, living conditions, disease history, family cancer history, smoking, alcohol drinking, dietary habits, frequency, amount of food intake, etc. Conditional logistic regression with maximum likelihood estimation was used to obtain Odds ratio (OR) and 95 % confidence interval (95% CI), after adjustment for potential confounders.RESULTS: In the preliminary analysis of the ongoing study, we recruited 291 pairs of cases and controls in Dafeng and 240 pairs of cases and controls in Ganyu,respectively. In both low-risk and high-risk areas, EC was inversely associated with socio-economic status, such as level of education, past economic status and body mass index. However, this disease was more frequent among those who had a family history of cancer or encountered misfortune in the past 10 years. EC was also more frequent among smokers, alcohol drinkers and fast eaters.Furthermore, there was a geographic variation of the associations between smoking, alcohol drinking and EC risk despite the similar prevalence of these risk factors in both low-risk and high-risk areas. The dose-response relationship of smoking and smoking related variables,such as age of the first smoking, duration and amount were apparent only in high-risk areas. On the contrary, a dose-response relationship on the effect of alcohol drinking on EC was observed only in low-risk areas.CONCLUSION: The environmental risk factors, together with genetic factors and gene-environmental interactions might be the main reason for this high-risk gradient in Jiangsu Province, China.